Strategic Goal: Goal 3: Advance Translational Research

Point of care detection of rare cells in blood

Laboratory analyses at the bedside or in the hinterlands can reduce the cost and increase the capture of disease states in underserved populations. The injection of a blood draw directly into a portable device that requires no further operator interventions is a Critical Challenge. With today’s automated chemistry and a miniaturized flow cytometer this challenge could be met.

Submitted by (@nhlbiforumadministrator)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Critical Challenge (CC)

Details on the impact of addressing this CQ or CC :

Although portable flow cytometers exist, they are not equipped with chemical automation and rare-cell enrichment capability. An integrated system could be applied to multiple diagnostic goals. A sufficiently versatile design should be able to detect and enumerate specific cell populations at any level (not only rare cells) in the circulation — T-cell subsets in AIDS, for example.

Feasibility and challenges of addressing this CQ or CC :

Automated mixing and labeling, magnetic bioseparations, microfluidics, high-intensity LEDs and sensitive avalanche photodiodes can be combined to address this CC.

Name of idea submitter and other team members who worked on this idea : Paul Todd

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Strategic Goal: Goal 3: Advance Translational Research

To find specific medical therapies to treat the wide array of human vascular malformations and vascular tumors.

Vascular malformations and vascular tumors, together referred to as vascular anomalies, comprise a complex and wide array of diseases in which there is a fundamental disruption in blood and lymphatic vasculature. The lesions disrupt organ function, destroy tissue, cause bleeding, increase infections and can threaten life. At present, there are some medical therapies but none are specifically targeted to an underlying ...more »

Submitted by (@joyce.bischoff)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Critical Challenge (CC)

Details on the impact of addressing this CQ or CC :

Deciphering the cellular and molecular basis of human vascular anomalies will have a critical impact for patients with these lesions and it will also have a broad, far-reaching impact on cardiovascular research because the mechanisms and insights learned from these specific vascular anomalies will teach us the fundamental rules that are needed, and must be followed, to build and maintain a stable functional vasculature in humans. This will have an impact on a variety of areas of research including regenerative medicine.

Feasibility and challenges of addressing this CQ or CC :

With the enormous advances in next generations sequencing technologies, the time is ripe for a concerted push to find the gene mutations that cause human vascular malformations and vascular tumors, both the most common and the rare. Cellular models for human endothelial cells are vastly improved and far superior to murine endothelial models, making research on patient-derived cells highly feasible.

The challenges will be to develop animal models of the individual human vascular anomalies that reflect as closely as possible the critical and specific features of the vascular malformation or vascular tumor. Such animal models, as well as relevant cellular in vitro models, would then be ideal for screen drug libraries for ability to reverse or slow the formation of the malformation or tumor. Such drugs might then be candidates to test in pilot clinical trials.

Name of idea submitter and other team members who worked on this idea : Joyce Bischoff

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Strategic Goal: Goal 2: Reduce Human Disease

Anemia, oxygen delivery, and red blood cell transfusion

In neonatal, pediatric, and adult patients with critical illness, what is the best means to identify: (1) the degree to which anemia contributes to insufficient oxygen (O2) delivery and (2) the likelihood that O2 delivery will be improved by red blood cell (RBC) transfusion? These questions are most relevant to critically ill populations that exhibit unique physiology, including those with low cardiac output (cardiac ...more »

Submitted by (@nareg.roubinian)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

In the critically ill, RBC transfusion is indicated to improve O2 delivery. Although RBC transfusion increases hemoglobin concentration (Hb) and thereby blood O2 content, it does not necessarily follow that O2 delivery to tissues is likewise increased. Current approaches to transfusion decision making in critical care settings maintain an ‘adequate’ RBC mass well above a level that may limit tissue O2 delivery. With improved understanding of vascular signaling and gas transport by RBCs and of the array of defects comprising the RBC ‘storage lesion’, we appreciate that this strategy must be balanced by consideration that: (1) donor and recipient RBCs do not exhibit similar physiology and (2) RBC transfusion may cause harm (beyond transfusion reactions and transmission of infection) – and that this harm appears progressive with: transfusion volume, frequency and donor exposure. As such, ‘restrictive’ Hb thresholds for RBC transfusion are appreciated to be at least non-inferior to ‘liberal’ Hb thresholds for a broad array of conditions. A paradigm shift is emerging in approach to the critically ill, with re-consideration of the ‘Hb trigger’ strategy, itself. Ideally, the decision to transfuse should be based upon individual and context-specific consideration of the degree to which anemia contributes to tissue O2 delivery.

Feasibility and challenges of addressing this CQ or CC :

We need to identify specific physiologic endpoints linked to outcomes as well as determine the appropriate thresholds for these goals. We must improve current means to assess functionality of the circulating RBC mass and its specific relationship to tissue O2 delivery in both humans and animal models. Approaches to resolve this gap could be conducted in the following areas during the next 3-5 years (studies may be independent or ancillary to clinical transfusion trials). Examples include but are not limited to the following: (1) clinical and translational research studies examining physiologic tolerance of acute and chronic anemia in the critically ill populations; (2) basic and clinical research exploring accuracy, precision and reliability of novel approaches to quantify and monitor O2 consumption and delivery (global/regional). Investigations should also determine the relationship of these measures to clinically relevant patient outcomes, both global (mortality, ventilator dependence, length of stay, etc.) and organ-specific; and (3) studies evaluating the process of transfusion decision making in the setting of critical illness.

Name of idea submitter and other team members who worked on this idea : Nareg Roubinian, MD and Naomi Luban, MD for the 2015 NHLBI State of the Science in Transfusion Medicine.

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Strategic Goal: Goal 2: Reduce Human Disease

How can we increase the pharmaceutical clinical research of targeted therapies in pediatric PAH patients, including encouraging

Clinical research, especially randomized pharmaceutical clinical trials, poses many unique challenges compared to research in adult subjects. In pulmonary arterial hypertension, a disease characterized by high blood pressure of the lungs with increased pulmonary vascular resistance leading to right ventricular failure, there are 12 FDA-approved PAH-targeted therapies for adults. None of these medications are currently ...more »

Submitted by (@katherinek)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Critical Challenge (CC)

Details on the impact of addressing this CQ or CC :

Pulmonary arterial hypertension is a heterogeneous condition generally characterized by high blood pressure in the lungs and increased pulmonary vascular resistance that leads to right heart failure if left untreated. Though some causes of PAH are seen in both adult and pediatric populations, some etiologies are seen exclusively in pediatric populations, including persistent pulmonary hypertension of the newborn, bronchopulmonary dysplasia, lung hypoplasia, and alveolar capillary dysplasia. Despite these differences in disease etiology, and known physiologic differences in pediatric populations, inhaled nitric oxide (iNO) in the acute setting is the only approved medication for PAH treatment in children. A number of issues have decreased pediatric PAH pharmaceutical research, including protection of the pediatric population as vulnerable subjects, principle of scientific necessity, balance of risk and potential benefit, parental consent/child assent, and feasibility of pediatric clinical trial design and implementation. Encouraging clinical trials of existing adult medications and potentially emerging, novel agents specifically for pediatrics—either through direct sponsorship or regulatory incentives—would not only lead to better outcomes for pediatric PAH patients, but potentially to a better and more comprehensive characterization of the developing pulmonary vascular system and right ventricle.

Feasibility and challenges of addressing this CQ or CC :

Several challenges exist for addressing this critical challenge. First, there are a number of differences between conducting clinical research in pediatric populations compared to adult populations. This not only includes the broad items referenced above, but items as noted by Rose and colleagues related to clinical trial design and analysis including (1) accepted age-matched normal ranges for laboratory values; (2) requirements for the validation of clinical endpoints for the assessment of efficacy and safety; and (3) standards for long-term safety monitoring and pharmacovigilance (Rose K, et al. NEJM 2005). Sponsorship of this type of clinical research is a second concern, which could either be mitigated by direct support from the National Institutes of Health of pediatric PAH clinical trials or in regulatory changes incentivizing pediatric clinical research in rare diseases.

Name of idea submitter and other team members who worked on this idea : Katherine Kroner, Michael Patrick Gray, PHA

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Strategic Goal: Goal 2: Reduce Human Disease

Optimizing Cardiovasular (CV) Prevention Medicine Use

Heart attacks and strokes cause substantial morbidity and mortality, while implementation of cholesterol and other CV prevention guidelines remain low. Proposed NCQA on-statin in the last year among those with DM was 46% in national field testing, and about 75% in Kaiser Permanente (KP). KP has had some success overcoming barriers to statin, aspirin, and blood pressure medicine adherence. If the nation as a whole is ...more »

Submitted by (@ronald.d.scott)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Critical Challenge (CC)

Details on the impact of addressing this CQ or CC :

Improving treatment rates to CV guidleines improves the population health and can be cost saving to the system. Currently statin use among DM and in those with ASCVD Risk >= 7.5% is about 40%. If treatment improved to 60 or 80% many CV avents would be averted and downstream cost savings.

Feasibility and challenges of addressing this CQ or CC :

KP has achieved blood pressure control rates of about 90% demonstrating possibility of high control / treatment rates. Improving treatment rates where there is a treatment gap in cost saving CV prevention should be a priority.

Name of idea submitter and other team members who worked on this idea : Ronald D Scott, MD. Kaiser Permanente Integrated Cardiovascular Health Team

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Strategic Goal: Goal 2: Reduce Human Disease

In pulmonary arterial hypertension (PAH), how can right ventricular function be improved in the setting of increased afterload

Pulmonary arterial hypertension (PAH) is a complex, progressive condition characterized by high blood pressure in the lungs and restriction of flow through the pulmonary arterial system. Significant improvements have been made in medical management with through approved pulmonary vasodilator therapies. However, long-term right ventricular afterload reductions have still not yet been achieved. The process by which the ...more »

Submitted by (@katherinek)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

Understanding of many components of the PAH disease state have evolved significantly in the past thirty years. When initially described by an NIH registry, in a time where pulmonary transplantation was the only treatment for PAH, the average life expectancy of PAH patients was estimated to be 2.8 years. Since then, 12 PAH-targeted therapies have been approved by the FDA; these therapies primarily act by dilating the pulmonary arteries in order to allow blood to flow easier through the pulmonary vascular system. Despite these advances and complex therapies, long-term afterload reduction is not achievable in most PAH patients. Patients continue to die from right ventricular failure, highlighting the important relationship of the pulmonary arterial system and right ventricle. Little is known about how and why the RV progresses from hypertrophy to full RV failure, the diagnostic signs indicating early RV failure, and how best to intervene to support the failing ventricle. Knowledge in this area is critical, however, as the RV is able to recover in many patients with severe PAH after lung transplantation. The relationship between the lung vasculature and cardiac function, and specifically a characterization of RV failure, was included as a research opportunity in the Strategic Plan for Lung Vascular Research in an NHLBI-ORDR Workshop Report (Erzurum S, et al. 2010).

Feasibility and challenges of addressing this CQ or CC :

The primary challenge of addressing this CQ on how right ventricular function can be improved in the setting of increased afterload is the comprehensive analysis and support that will need to be provided, spanning from basic to clinical science. To begin, strong support of biologic characterization of the right ventricle needs to be provided. The RV is distinctly different from the more comprehensively studied left ventricle (LV), and subsequently responds differently to changes in pressure, neurotransmitters, hormones, and pharmaceutical therapies to name only a few. However, when identified, these RV biologic distinctions can be further explored to develop a better understanding of RV failure and potential points of intervention.

Name of idea submitter and other team members who worked on this idea : Katherine Kroner, Michael Patrick Gray, PHA

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Strategic Goal: Goal 2: Reduce Human Disease

Evidence based approaches to Red Blood Cell transfusion

What are the optimal RBC transfusion thresholds for adult and pediatric cancer patients undergoing chemotherapy regimens that may improve functional status and quality of life?

Submitted by (@nareg.roubinian)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

Cancer patients undergo intensive medical and surgical therapies to treat their underlying disease. Treatment commonly results in anemia requiring RBC and platelet transfusions to support the patient through the hypoproliferative phase of chemotherapy. This is particularly true for those patients requiring hematopoetic stem cell transplantation (HSCT). Following therapy, cancer outpatients commonly receive RBC transfusions for weeks to months to maintain their functional status.

 

Common causes of death in patients with hematological malignancies and other cancers are infections and bleeding. A meta-analysis of clinical trials suggested that liberal transfusion is associated with greater risk of infection. Conversely, restrictive transfusion could adversely affect quality of life and functional status in oncology populations. In addition, pre-clinical and clinical studies support that concomitant anemia and thrombocytopenia significantly compound bleeding risk, and that hemostasis can be optimized in thrombocytopenia by maintaining a higher hematocrit. Although bleeding risks in relation to platelet transfusion thresholds are well studied in patients with hematological malignancy, optimal hemoglobin levels in thrombocytopenic patients are not known. Despite the significant allocation of blood components to cancer patients as a whole, RBC transfusion practices are not well studied within this group.

Feasibility and challenges of addressing this CQ or CC :

Randomized controlled clinical trials and other studies investigating optimal transfusion thresholds and other measures of practice are required to provide health care providers with evidence to guide one of the most common therapies administered in the setting of malignancy. The clinically important end points of well-designed studies could include: 1) quality of life and functional status for both inpatients and outpatients; 2) neurocognitive development in pediatric populations; 3) bleeding events / bleeding scores; 4) impact on immunity including immunomodulation and infection; 5) reconstitution of hematopoiesis; and 6) survival and/or recurrence of disease.. Besides a generalizable study population, certain target populations of interest are those with high risk disease, HSCT patients, patients undergoing radiation therapy, and pediatric patients.

 

There are >1.6 million new cases of cancer annually in the USA, including >50,000 with leukemia and >6,000 with HSCT. Cancer therapies are rapidly advancing in the era of genomics and immunotherapy. Capitalizing on the tradition of research in cancer, single and multicenter studies of RBC transfusion are feasible using randomized controlled designs in conjunction with clinical trials of chemotherapeutic regimens. The results of these studies will impact a large patient population’s quality of life, and may ultimately impact healthcare cost and blood demand.

Name of idea submitter and other team members who worked on this idea : Nareg Roubinian, MD and Naomi Luban, MD for the 2015 NHLBI State of the Science in Transfusion Medicine

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Strategic Goal: Goal 1: Promote Human Health

The Human Virome and Host Interactions in Heart, Lung, and Blood

What are the unknown elements of the human virome, and what host-virome interactions affect the heart, lung, and blood health and diseases? A major challenge has been the need for in vitro culture systems and animal models for studying the virome, which is a significant limitation that has forced current studies of the virome to be mostly descriptive. NHLBI has supported one research group to identify human virome and ...more »

Submitted by (@nhlbiforumadministrator)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

• The virome contains the most abundant and fastest mutating genetic elements on Earth. The human virome is constituted of viruses that infect host cells, virus-derived elements in our chromosomes, and viruses that infect the broad array of other types of organisms that inhabit us. The virome may influence the host in profound ways independent of classical viral disease. The immune system is continuously stimulated by chronic systemic viruses and this aspect of host-microbiome interactions appears specific to the virome. The virome is considered one of the drivers of idiopathic systemic inflammation that has been linked to many of the most severe public health threats, including cardiovascular diseases. Disruptions in immunity by immunosuppressing events can undoubtedly alter the interactions of the virome with the host. However, little research has been done in all of these aspects other than limited descriptive studies to identify the presence or composition of the human virome. The NHLBI Microbiome Working Group in June 2014 clearly identified under-representation of studies of the human virome. Identification and characterization of unknown viral elements of the human virome and research on the interactions with the host will allow exploration of their impact on heart, lung and blood health and diseases, including impact in the presence of immunosuppression with the host such as in AIDS or HIV infection.

Feasibility and challenges of addressing this CQ or CC :

This initiative is feasible because of new technologies that have been developed recently such as the deep sequencing techniques. The initiative is also timely in that research supported by the NIH Human Microbiome Program and other programs has allowed us to better understand microbiome, especially bacteria in and on humans, and we began to realize the magnitude of the virome. This initiative will attract more investigators to not only identify more elements of the virome but more importantly to understand the roles of the human virome in heart, lung and blood health and diseases, and eventually to help develop diagnostic and intervention strategies.

Name of idea submitter and other team members who worked on this idea : NHLBI Staff

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Strategic Goal: Goal 3: Advance Translational Research

Stem Cell Biology

There is a need to develop “designer platelets” and “designer red cells,” as well as facilitate large-scale production of these products for therapeutic and diagnostic use.

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Critical Challenge (CC)

Details on the impact of addressing this CQ or CC :

The reprogramming of adult stem cells has resulted in the generation of induced pluripotent stem cells (iPSCs) that can develop into any tissue of the body. These iPSCs ultimately may be used as a transplantable source of stem cells for a variety of hematologic diseases. Although this technology has enabled the generation of patient-specific or disease-specific stem cells that are also amenable to genetic manipulation, the major scientific hurdle has been the ability to create clinically meaningful functional blood products, including transplantable HSCs from differentiating iPSCs. The production of clinically functional blood products -- i.e. red blood cells derived from autologous iPSCs --could replace allogeneic products in highly immunized patients and the generation of megakaryocytes for patient-specific platelet production from iPSCs could drive significant progress in this area. Furthermore, disease-specific iPSCs could serve as targets for both drug development and drug screening in patients with rare hematologic disorders. In addition, support for scale-up and GMP processes, which are difficult to fund via the R01 mechanism will require specific grant opportunities tailored to infrastructure and process development.

Name of idea submitter and other team members who worked on this idea : Alice Kuaban on behalf of the American Society of Hematology (ASH)

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Strategic Goal: Goal 1: Promote Human Health

Iron Loss after Blood Donation and Its Effect on Donors’ Health

What is the effect of donation-induced iron deficiency on blood donor health?

Submitted by (@anne.eder)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

Blood donation removes iron, and frequent blood donors commonly have low or absent iron stores. Donation frequency remains the strongest predictor of iron depletion among all donors, after controlling for body mass, race/ethnicity, and polymorphisms affecting iron metabolism. Less well documented is the effect of iron depletion on blood donor health and well-being. Iron deficiency may have a broad spectrum of physical and neurologic consequences, including impaired work capacity, altered cognitive function, pica and restless legs syndrome. The prevalence, duration, and severity of these conditions in blood donor populations are poorly elucidated. In contrast, modest iron deficits may be protective against cancer and cardiovascular disease. Some investigators have demonstrated the feasibility to connect donor information with clinical databases to study whether donation behavior and iron status have long-term consequences for donor health.

Feasibility and challenges of addressing this CQ or CC :

Studying the short-term clinical impact of donation-induced iron deficiency presents logistical and methodological challenges. Many outcomes of interest are not observable by blood center staff under routine procedures; further, such studies are subject to selection bias due to donor failure to return to donate following low hemoglobin deferral or adverse outcomes they associate with donation. However, given the size and demographic diversity of donor populations, even uncommon outcomes can be successfully studied under a multi-center approach. A prospective approach that doesn’t condition enrollment or completion of the study on return to donate, may avoid the methodological pitfalls. A wide array of clinical or neurological outcomes can feasibly be studied with sufficient blood centers and/or donor follow-up.

Name of idea submitter and other team members who worked on this idea : Dana Devine PhD and Anne Eder MD PhD for the 2015 NHLBI State of the Science in Transfusion Medicine

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Strategic Goal: Goal 2: Reduce Human Disease

Blood Donor and Component Factors that Influence Clinical Outcomes of Transfusion

Are donor factors (age/sex), whole blood processing methods and/or red cell storage solutions associated with in-hospital mortality and/or other measures of transfusion efficacy or harm in patients who have received red cell transfusions?

Submitted by (@anne.eder)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

There is growing evidence that donor factors (age, race-ethnicity, and/or sex), method of whole blood processing, and/or the additive solution used for red cell storage could affect the quality of the red cell product and contribute to patient adverse events. For example, red cell rigidity and oxygen saturation varies between premenopausal women and postmenopausal women and men, suggesting that donor age and/or sex may be important factors affecting red cell quality and patient outcomes. A retrospective Canadian study suggested that older blood was associated with in-hospital mortality until 2006; however, after that time the risk of in-hospital mortality increased when fresher blood was transfused. This change coincided with introduction of the buffy coat method suggesting that whole blood processing methods may affect patient outcomes.

Feasibility and challenges of addressing this CQ or CC :

The most efficient way to explore these issues is through the use of large dataset that can link donor demographics, product processing and recipient transfusion and outcome data. Recipient datasets are available and the feasibility of linking blood donor and blood product information has been demonstrated, making it possible to address the research question stated above.

Name of idea submitter and other team members who worked on this idea : Dana Devine PhD and Anne Eder MD PhD for the 2015 NHLBI State of the Science in Transfusion Medicine

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Strategic Goal: Goal 2: Reduce Human Disease

Stem Cell Biology

There is a need to develop an artificial and functional hematopoietic stem cell (HSC) niche that allows for the expansion of repopulating HSCs.

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Critical Challenge (CC)

Details on the impact of addressing this CQ or CC :

Methods to expand hematopoietic stem cells have continued to be examined extensively because stem cell numbers in the graft are important for clinical outcomes following transplantation. These numbers are particularly relevant in umbilical cord blood (UCB) transplantation, where low numbers of stem cells are directly related to delayed hematopoietic and immune reconstitution. Improved HSC expansion strategies may significantly impact transplantation outcome, enabling broader applications beyond UCB transplantation. Furthermore, these strategies are also needed to realize the full therapeutic potential of genome editing technologies to correct hematopoietic stem cells derived from patients with hematologic disorders. Since efforts to expand HSCs in cytokine-supported liquid cultures have been largely unsuccessful, efficient expansion will require an appropriate context that is provided by the hematopoietic stem cell niche. Future studies must also evaluate how niche signals regulate stem cell function to optimize cell expansion, and proper humanized mouse models must be developed to help predict stem cell function and regulation by the niche.

Name of idea submitter and other team members who worked on this idea : Alice Kuaban on behalf of the American Society of Hematology (ASH)

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